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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1961
Report Date:
1961

Materials and methods

Principles of method if other than guideline:
BASF-Test: Test substance was applied by gavage in a 1.25 - 2.5% aqueous traganth suspension. Mortality, clinical signs, and pathology of animals was investigated. Additionally, methemoglobin and Heinz bodies were investigated.
GLP compliance:
no
Test type:
standard acute method

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
cat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: see table 1

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: aqueous traganth suspension
Details on oral exposure:
1.25 - 2.5% aqueous traganth suspension were used.
Doses:
10, 25, 50, 100, 200, and 400 mg/kg bw
No. of animals per sex per dose:
10: 1 male; 2 female
25: 0 male; 3 female
50: 1 male; 2 female
100: 6 male; 5 female
200: 2 male; 5 female
400: 1 male; 1 female
Control animals:
no
Details on study design:
One application of 1.25 - 2.5% aqueous tragacanth suspension were used.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 50 mg/kg bw
Based on:
test mat.
Mortality:
10: 0/3
25: 1/3; 1 female after 6 days
50: 0/3
100: 7/11; 3 male; 4 female
200: 6/7; 1 male; 5 female
400: 2/2; 1 male; 1 female
Clinical signs:
After treatment animals were atonic, staggering and mostly vomitting.
Animals had mydriasis, showed no pupil reaction to light and had a reduced corneal sensibility. The animals were amblyopic or suffered from blindness. These chacteristics could be observed down to 25 mg/kg and seemed to be irreversible in high dose levels (200 mg/kg bw).
Blood:
Unfortunately not in all animals of the experiment the percentage of MetHb/Hb was determined. 9 and 11% MetHb were observed in the 50 mg/kg bw dose group, 11-17% in the 100mg/kg dose group and in one animal of the 200 mg/kg bw dose group 15% MetHb was observed. This moderate increase (>10%, <40%) in methemoglobinaemia was accompanied by a significant dose dependend increase in Heinz-bodies (up to 94%). The formation of Heinz-bodies is known to be a more closely related indicator of methemoglobinaemia.

Therefore the potency for MetHb formation of MDA has to be evaluated as moderate. The mortality observed in this experiment was not primarily related to MetHb formation.
Urinalysis: proteinuria
Body weight:
see table 1
Gross pathology:
Hepatotoxicity:
One day after treatment damage of the liver was observed with a disturbed excretion of bromosulphthaleine. Also the activity of serume glutamate-pyruvate-transaminase was disturbed. High bilirubin levels in urin and icterus were observed. Damage of liver functions seemed to be reversible, but occured beginning with 10 mg/kg bw.
Kidney:
High urea levels were observed in blood, accompanied with high protein, leukocytes, erythrocytes levels in urine. Additionally kidney epithelial cells and granulated cylinders were verified in urine. These characteristics also occured from the dose level 10 mg/kg bw.
Other findings:
Ophthamologigal reevaluation revealed strong mydriasis with no or weak reactivity toward light pulses. Blindeness was diagnosed by unsecure motion of the animals. Animals partly exhibited a spastic constriction of arteries (diameter decreased to approx. half) 43 and 22 days following application of the test substance.

Any other information on results incl. tables

Table 1: Body weights of cats (at study initiation and determination), Met-Hb levels (in %), Heinz bodies (% erythrocytes) and mortalities (day after application).

Dose (mg/kg)

Bodyweight (kg)

Bodyweight (kg)

Methaemoglobine (%)

Dead after days

Killed after day  Heinz bodies (%)  characteristic intoxication

study init.

end det.

     

10

3.3

3.2

-

-

 -  15  -

2.7

2.6

-

-

 -  8  -
   2.8 2.6   -  -  -  9  -
 25  2.5 2.5   -  -  29  28 mydriasis up to blindness, nephrosis
   2.3 2.0   -  -  31  30 mydriasis up to blindness, mild liver and kidney damage 
   2.6 2.2   -  6    24 mydriasis up to blindness, mild ikterus
 50  2.6 2.4   -  -  54  47 mydriasis up to blindness, mild hepatitis and nephrosis 
   2.2 2.0   9  -  54  41 mydriasis up to blindness, hepatitis
   2.2 2.1   11  -  43  76 mydriasis up to blindness
 100 2.5  2.2   -  -  -  - mydriasis up to blindness, ikterus
   3.3 3.1   12  5    14 -73 mydriasis up to blindness, ikterus, liver and kidney damage 
   2.3 2.2   -  4    - mydriasis up to blindness (?), ikterus, mild kidney damage 
   2.5 2.3   -  2    - mydriasis up to blindness, kidney damage 
   3.9 3.9   13  2    27 -67 mydriasis up to blindness, mild ikterus, mild liver and kidney damage 
   3.6 3.0   11  -  71  26 -45 mydriasis up to blindness, nephrosis 
   3.1 2.3   -  -  71  10 -94 mydriasis up to blindness, nephritis and nephrosis
   3.3 2.9   -  -  98  35 -46 mydriasis up to blindness, nephritis  
   2.5 2.3   17  2    35 -46 mydriasis up to blindness, kidney damage 
   2.9 2.7   -  1    - mydriasis up to blindness, mild ikterus,  
   2.6 2.4   11  3    18 -41 mydriasis up to blindness, mild ikterus, liver and kidney damage
 200 2.9  2.6   -  1    - mydriasis up to blindness, ikterus, kidney damage  
   1.7 1.6   15  3    71 mydriasis up to blindness, severe ikterus, liver and kidney damage
   2.9 2.4   -  2   mydriasis up to blindness, mild ikterus, kidney damage
   3.6 3.1   -  -  -  12 -83 mydriasis up to blindness
   2.8 2.8   -  1    - mydriasis,
   3.3 3.0   -  2    - mydriasis up to blindness,
   2.8 2.6   -  4    - mydriasis up to blindness, ikterus, liver/kidney damage
 400 3.5  3.2   -  2    - mydriasis,
   2.7 2.7   -  3    6 -24 mydriasis, ikterus, liver/kidney damage

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria